Appropriate drug therapy for attention-deficit hyperactivity disorder (ADHD) requires special consideration of lifestyle and life span comorbidity. (1) dI-Methylphenidate (MPH) is a drug of choice for ADHD; (2) Substance/alcohol abuse and dependence is over-represented in adolescent and adult ADHD, especially in women; (3) A pilot study revealed a novel MPH-ethanol metabolic drug interaction, wherein ethanol combines with MPH to form ethylphenidate (ETPH); and (4) the ethanol also appeared to inhibit MPH metabolism (especially in the female subjects; women have been reported to exhibit reduced first-pass metabolism of ethanol). Given these considerations, the potential therapeutic and toxicological significance of the MPH-ethanol interaction is proposed for investigation. SPECIFIC AIM 1 is to test the hypothesis that the enantiomers of the metabolite ETPH contribute to the neuropharmacology of concomitant MPH-ethanol. Monoamine transporter inhibition and mouse behavioral screens will be used for this assessment. SPECIFIC AIM 2 will test the hypothesis that ETPH will be formed enantioselectively. Enantiospecific gas chromatography-mass spectrometry (GC-MS)-negative ion chemical ionization will be used to simultaneously quantitate d-MPH, I-MPH, d-ETPH and I-ETPH from serial plasma samples. Healthy human volunteers-eight men and eight women--will participate in these pharmacokinetic studies. SPECIFIC AIM 3 (a) will ask what extent the MPH-ethanol interaction increases MPH blood concentrations in men vs. women; (b) will test the prediction that ethanol will not only elevate total plasma MPH levels, but also reduce the plasma d-MPH/I-MPH ratio; and (c) will test the hypothesis that the order of administration of ethanol relative to MPH influences the extent of this drug interaction (in the same order-dependent manner that has been reported for the cocaine-ethanol interaction which forms cocaethylene and can inhibit cocaine metabolism). The findings will serve to broaden our understanding of the toxicological consequences of MPH-ethanol coabuse and contribute to the rational emergency management of this common concomitant drug overdose. Further, the results will be used to support recommendations for optimal drug individualization in the treatment of ADHD, e.g., dextroamphetamine vs. MPH; dI-MPH vs. d-MPH; immediate-release MPH vs. extended-release MPH; or adjustment of MPH.